The role of the pineal gland hormone melatonin in the regulation of estrogen receptor (ER) activity and the growth of MCF-7 human breast cancer cells is being studied in vitro and in vivo. We have shown that melatonin rapidly increases the cytosocil and nuclear estrogen receptor activity of human breast cancer cells, a process which is dependent upon protein synthesis. We have also shown that melatonin will increase the ER activity of normal hamster uterine activity in vivo and in vitro in an analogous manner. We are presently studying the mechanism of this induction, and the physiochemical changes in the receptor which accompany induction, including sedimentation properties on sucrose gradients, molecular weight changes by PAGE and salt extraction properties. We are studying the binding of melatonin induced ER to DNA, and to nucleoacidic protein acceptor sites, and are also analyzing the effect of ER induction on growh of MCF-7 cells in vitro and MCF-7 solid tumors in vivo. These studies will further define the importance of melatonin in the regulation of hormone dependent breast cancer. We are also studying the secretion of plasma melatonin in women with hormone dependent breast cancer, women at high risk for breast cancer, and normal subjects. We have found a highly significant inverse correlation between the plasma level of melatonin and the quantity of estrogen or progesteron receptor in human breast cancer. This correlation is independent of age, menopausal status, stage of disease, or plasma levels of steroid hormones. We are studying the plasma melatonin diurnal rhythm in women at high risk for breast cancer in normal subjects to determine whether this abnormality of melatonin secretion precedes, or is a consequence of, breast cancer. Preliminary studies suggest plasma melatonin may be an important factor in determining the estrogen receptor content of human breast cancer.